Oral mucositis is a significant side effect of cancer therapy and bone marrow transplantation that is not adequately managed by current approaches (Sonis, 1993a, "Oral Complications," In: Cancer Medicine, pp. 2381-2388, Holland et al., Eds., Lea and Febiger, Philadelphia; Sonis, 1993b, "Oral Complications in Cancer Therapy," In: Principles and Practice of Oncology, pp. 2385-2394, DeVitta et al., Eds., J. B. Lippincott, Philadelphia). Oral mucositis is found in almost 100% of patients receiving chemotherapy and radiotherapy for head and neck tumors and in about 90% of children with leukemia. About 40% of patients treated with chemotherapy for other tumors develop oral problems during each exposure to the chemotherapeutic agent (Sonis, 1993b, supra). Additionally, approximately 75% of patients undergoing bone marrow transplantation, both autologous and allogeneic, develop mucositis (Woo et al., 1993, Cancer 72:1612-1617). Current estimates indicate that about 400,000 patients suffer from oral mucositis annually in the United States alone (Graham et al., 1993, Cancer Nursing 16:117-122). Given that patients often receive multiple cycles of chemo- and/or radiotherapy, there are an estimated 1,000,000 incidences of oral mucositis per year in the United States.
The incidence of oral mucositis varies depending on the type of tumor, age of the patient, and state of oral health. The therapies used in these different tumors are an important factor with the very aggressive chemotherapy protocols used in bone marrow transplant being associated with a high incidence of oral mucositis. Younger patients have a higher incidence, which may be due to their more rapid epithelial cell turnover, and hence susceptibility to cytotoxic drugs (Sonis 1993a, supra).
Incidence is also related to the choice of chemotherapeutic agent, with agents such as carmustine (BCNU), chlorambucil (Leukeran), cisplatin (Platinol), Cytarabine, doxorubicin (Adriamycin), fluorouracil (5-FU), methoxetrate (Mexate) and plicamycin (Mithracin) being known for their direct stomatotoxic potential (Sonis, 1993b, supra) and hence incidence of oral mucositis. The increasing use of aggressive infusion protocols is also associated with an increased incidence of oral mucositis.
Oral mucositis is initiated by the cytotoxic effects of chemotherapy and/or radiotherapy on the rapidly dividing epithelial cells of the oropharyngeal mucosa, and is exacerbated by infection with both endogenous oral flora and opportunistic bacterial and fungal pathogens. Complications related to oral mucositis vary in the different patient populations affected, but include pain, poor oral intake with consequent dehydration and weight loss, and systemic infection with organisms originating in the oral cavity (Sonis, 1993b, supra). The pain associated with oral mucositis may be severe requiring narcotic analgesics, and the difficulty in eating can result in patients receiving total parenteral nutrition. The damaged oral epithelium and defective immune response often found in these patients offers a ready route for entry of organisms from the mouth into the systemic circulation. This is a major concern due to the potential for sepsis, and injectable antibiotics are used when signs of systemic infection are observed. Due to these complications, oral mucositis can be a dose-limiting toxicity of radiation or chemotherapy treatment, resulting in inadequate therapy for the cancer.
A variety of approaches to the treatment of oral mucositis and associated oral infections have been tested with limited success. For example, the use of an allopurinol mouthwash, an oral sucralfate slurry, and pentoxifylline were reported in preliminary studies to result in a decrease in mucositis. Subsequent randomized and controlled studies, however, have failed to demonstrate any benefit to treatment with these agents (Loprinzi et al., 1995, Sem. Oncol. 22 Supple. 3):95-97; Epstein & Wong, 1994, Int. J. Radiation Oncology Biol. Phys. 28:693-698; Verdi et al., 1995, Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 80:36-42).
Other therapies have been directed at decreasing oral flora and the extent of infection of oral ulcerations. Systemic treatment with G- and GM-CSF has been shown to result in a decreased incidence of oral mucositis, presumably by allowing for more rapid neutrophil recovery and thus an improved ability to combat infection, although it has been postulated that the CSFs may have a more direct effect on the oral mucosa (Chi et al., 1995, J. Clin. Oncol. 13:2620-2628). In one study, GM-CSF was reported to exacerbate mucositis. (Cartee et al., 1994, Cytokine 7:471-477). Benzydamine hydrochloride, a nonsteroidal drug with analgesic and antimicrobial properties, has been studied both in patients undergoing radiation therapy and in patients receiving intra-arterial chemotherapy (Epstein et al., 1986, Oral Surg. Oral Med. Oral Pathol. 62:145-148; Epstein et al., 1989, Int. J. Radiation Oncology Biol. Phys. 16:1571-1575).
Chlorhexidine, an antimicrobial mouth rinse, has also been used extensively in the treatment and prevention of oral mucositis (Ferretti et al., 1990, Bone Marrow Transplan. 3:483-493; Weisdorf et al., 1989, Bone Marrow Transplan. 4:89-95). It has been noted however that the efficacy of chlorhexidine is significantly decreased in saliva, and that this compound is relatively ineffective against the Gram negative bacteria that tend to colonize the oral cavity in patients undergoing radiation therapy (Spijkervet et al., 1990, Oral Surg. Oral Med. Oral Pathol. 69:444-449). In addition, at least one study has shown that the use of chlorhexidine may be detrimental and result in a higher incidence of mucositis (Foote et al., 1994, J. Clin Oncol. 12:2630-2633).
Several studies have shown that the use of a vancomycin paste and antibiotic lozenges containing polymixin B, tobramycin and amphotericin B in patients undergoing myelosuppresive chemotherapy or radiation therapy can result in a decrease in oral mucositis and in the incidence of sepsis due to alpha hemolytic streptococci (Barker et al., 1995, J. Ped. Hem. Oncol. 17:151-155; Spijkervet et al., 1991, In: Irradiation Mucositis, Munksgaard Press, pp. 43-50). Despite the clear need for therapeutic agents to treat oral mucositis, no drugs are currently approved for this indication. As a result, there is no standard treatment for this disorder.
Topical application of agents useful to treat oral diseases such as oral mucositis presents unique problems. For example, due to salivation and/or food or fluid intake, it is oftentimes extremely difficult to attain sufficient mucoadhesion and residence time in the mouth for the agent to be effective. Topical application of peptides is even more problematic, as the peptides must be stable to proteolytic enzymes resident in saliva. Other difficulties associated with topical oral application of drugs include tooth discoloration and patient compliance. Oral formulations providing good mucoadhesion and residence time in the mouth while at the same time providing high levels of patient compliance are not readily available.
Hence, the availability of compositions and methods for treating oral mucositis which exhibit broad spectrum antimicrobial activity, good stability, mucoadhesion and residence time in the mouth and which yield high levels of patient compliance are extremely desirable, and are therefore objects of the present invention.